Project Summary/Abstract: The overall aim of this project is to further develop a novel gemcitabine-ibandronate conjugate alone and/or as part of a combination therapy for the treatment of osteosarcoma and associated metastases. The conjugate consists of chemically linked anticancer antimetabolite Gemcitabine and the bone-homing bisphosphonate Ibandronate. The novel conjugate directly addresses the limitations of conventional osteosarcoma therapies by concentrating drug at the site of bone lesions and offers potential improvements in efficacy and side-effect profiles. This targeted delivery design provides for an effective concentration of a chemotherapy agent in bone while maintaining low systemic levels. In Phase 1 we have demonstrated this conjugate offers synergies with Docetaxel and enables a 10-fold lower exposure to Gemcitabine while inhibiting cancer growth at a similar level. As an added benefit, the drug appears to strengthen the bones and may reverse the deterioration of bone associated with bony malignancies. This project looks specifically at optimizing the ability of the Gemcitabine-Ibandronate conjugate alone or in combination with Docetaxel to treat a mouse model of osteosarcoma as compared to treatment with free Gemcitabine in combination with Docetaxel and tests the drugs in spontaneous osteosarcoma in a canine clinical trial. The specific aims of this Phase II project assess the tissue distribution and effects of the novel bone targeting conjugate?alone and in combination with Docetaxel on local tumor burden, bone lysis and metastatic burden in an orthotopic osteosarcoma syngeneic murine model and spontaneous canine osteosarcoma. The successful completion of this project will guide the further development of this promising drug design concept and will ultimately result in therapeutic agents that will significantly improve cancer patient care, resulting in increased quality of life and survival.